Gene4Denovo2: an updated platform for human de novo mutations discovery and interpretation

Abstract De novo mutations (DNMs) drive evolution and increase biodiversity, yet concurrently act as a cryptic cause of numerous genetic diseases. Here, we present Gene4Denovo2 (https://genemed.tech/gene4denovo2/), an updated version of the Gene4Denovo, aiming to provide a more comprehensive DNM datasets and their interpretations. The key improvements include the following: (i) We have substantially expanded the number and scope of DNMs, associated samples, and phenotypes. Specifically, Gene4Denovo2 now contains 1 626 050 DNMs from 130 439 individuals across 96 phenotypes. Moreover, clinical information covering nearly 1000 items has been added for 448 096 individuals, including those with DNMs and their unaffected family members. (ii) We have introduced new features to assist in the evaluation of DNMs, including support for ACMG rating and the addition of gene prioritization scores for rapid classification and filtering of candidate genes. (iii) An upgraded analysis interface allowing flexible annotation configuration and a significant expansion in the number of annotatable datasets. Additionally, a new integrated tool enables DNMs calling from family-based sequencing data. In summary, Gene4Denovo2 provides a more extensive collection of DNMs, enhanced annotation capabilities, and upgraded analysis tools, which will facilitate a deeper exploration of the role of DNMs in disease pathogenesis.